Trading the Stethoscope for the Nanoscope

In 1981, Professor Lieber had his sights set on medical school and a long career as a physician. But just as he was about to head off to medical school, he finally realized that his true calling was research and decided to pursue his passion for chemistry at Stanford, where he earned his Ph.D. That decision thirty years ago—Lieber calls it his “unintentional design”—culminated in Professor Lieber being rated by Thompson Reuters as the #1 Chemist by achieving “the highest citation impact scores for chemistry papers (articles and reviews) published since January 2000 through 2010…Citation impact (citations per paper) is a weighted measure of influence that seeks to reveal consistently superior performance” (Thompson Reuters).

Professor Lieber is currently the Mark Hyman Professor of Chemistry, with a joint appointment in the Harvard School of Engineering and Applied Sciences, and the mastermind behind some of the most revolutionary nanoscopic materials. Such materials have far-ranging implications in the rapidly developing fields of computing and health science.

Just how did chemistry lead him into the fields of nanoscience and nano-computing? It began at Columbia University, where as assistant and associate professor he studied low-dimensional materials. He continued his research in these fields when he moved to Harvard in 1991, where he also investigated quasi 1-D or 2-D solids and anisotropic (materials whose properties are directionally dependent) molecules. These quasi 1-D materials are “akin to viewing a crystal of DNA as a 1-D object—just a linear strand of information.” Quasi 1-D materials are multi-dimensional materials with strong bonds in only one dimension, hence, the material properties are primarily determined by this one dimension.

However, his research suddenly took a turn during the early 1990s while collaborating with Professor David R.

Nelson, Arthur K. Solomon Professor of Biophysics and Professor of Physics and Applied Physics, on the “esoteric problem of magnetic vortices…and using high energy ions to create damage tracks in solids.” Professor Lieber determined that instead of using the high energy, giga-electron volt ions blasting through the material to create these tracks, he could instead chemically design and engineer crystals that could then be used to synthesize one-dimensional nanowires.

Lieber’s work soon “led to a change in interests” after he published his first paper describing “the synthesis of one-dimensional wires.” As he paused to take a step back he began to visualize future, unintended, yet much more interesting implications of his work. At the time, researchers were excited about the potential of new nano-sized materials called quantum dots—small 3-D boxes that trapped electrons within and could be manufactured in different sizes, thought to have many applications in energy and other sciences.

Eureka!

Lieber, however, had the foresight to recognize that in order to sustain large scale complex nanosystems “you needed things to connect” and communicate. Quantum dots were individual objects, like separate M&M candies in a bag. Lieber reasoned that “one- dimensional systems would [facilitate] the smallest connections” possible, and focused his recently-developed ability to synthesize 1-D wires towards the grand goal of achieving a complete nanosystem network connected by his nanowires.

Lieber rushed over to his graduate student, Peidong Yang, and yanked him away from his thesis project, urging him to direct his efforts to this exciting research. It may have seemed a long-shot for any Ph.D. student to suddenly switch the focus of his thesis, but their boldness paid off and Lieber and Yang went on to make seminal discoveries in their field of work.

With pride, though tinged with a sense of irony, Lieber lauds Yang, as “one of my best students,” who, as Professor of Chemistry at University of California, Berkeley, is now “one of my main rivals.”

Nanocomputing

In his famous 1960 talk to the American Physics Society, the renowned Nobel Laureate Richard P. Feynman called for a new era in science, in which he dreamed of making computers small enough that one could essentially build a computer on the head of a pin.

Today, 50 years later, Lieber’s group is turning this dream into a reality. This February, he and his collaborators, the MITRE Corporation—a not-for-profit research organization—published an article in Nature entitled “Programmable nanowire circuits for nanoprocessors.” They developed the first programmable nanoprocessor that could perform arithmetic and logical functions—a miniature version of the CPUs in our computers.

According to Lieber, this research represents the key to developing more complex nanotechnology. This new programmable nanoprocessor, that can be functionalized and execute commands, “entails making something that processes information.” Lieber is convinced that nanoscience will be useful “if we take the ideas of organization, encoding information through synthesis in the same way that we translate DNA” in the field of biology.

A decade ago, Lieber and his group were working on nanowires and developing the chemistry to synthesize complex networks of nanowires because “no one really had ways of making these materials.” Only now have synthesis reactions advanced enough to be able to create complex structures of interacting nanowires that can begin to process data and communicate.

The Challenge

It has been a long road for Lieber; he recalls giving a talk in Europe some years ago when a representative from IBM challenged him: “How can you justify what you are doing?” Lieber was confident, yet careful in his response, and acknowledged that although the use of nanowires was in its infancy, and that they could not yet compete with the fastest computer chips on the market, in years to come nanowires could develop into something much more complex, maybe never reaching the speed of modern computers, but rather, carving out their own unique space of nanoscopic applications.

Learning from Biology

Lieber believes that “the way that nanoscience is going to be beneficial, rather than just continuing trends from the microelectronics industry and scaling things down, is to take ideas of organization that biology uses to hierarchically organize things, taking advantage of different interactions for encoding information.”

Although linking nanowires together to form complex, microscopic nanosystems sounds like quantum leaps into the future, for Lieber, with his background in chemistry and biology, all this seems crystal clear. In graduate school he studied the flow of electrons in a cascade of proteins in cells, and with his unique insight he sees computing and nanowires as a familiar process of just “transferring electrons.”

Life-Saving Research

Despite his pre-med intentions and last-minute turn away from a medical career, Lieber’s passion to pursue meaningful research could potentially have far greater implications for medicine, and his new technology could reach out and save far more lives than he could have had as a doctor.

The "kinked hairpin".

Currently, one major focus of Lieber’s team is the so-called “kinked hairpin,” a nano-sized probe to peek into the inner workings of individual cells. Trading the stethoscope for his new nano-scope, Lieber has reached a new milestone. The culmination of decades of innovative research has led to the creation and development of an entirely new science and methodology for making nanowires and structured nanowires—ones with kinks, turns, and angles. Built upon the breadth of Lieber’s groundbreaking research over the past several years, scientists are now able to contemplate and develop the advanced complex nanostructures.

These tiny hairpin structures are miniaturized transistors covered with phospholipids that can slip into cells and scan for a multitude of molecules or voltage gradients. An immediate application could be for drug development, using the probe to track drug concentrations within a cell to determine efficacy and longevity while also monitoring for possible toxic levels of concentration.

Do labs need to invest in another piece of expensive equipment to benefit from Lieber’s work? Displaying a keen marketing and business acumen, Lieber tapped into his experience working as a biologist purifying proteins—biologists like the equipment and microscopes they already have. So, rather than create an entirely new device, Lieber developed the probe as an add-on to existing microscopes.

The next step for Lieber is the development of 2-hairpin probes that simultaneously monitor the cell interior with one hairpin and the exterior with the other, to determine the effect of gradients in the intracellular and extracellular regions.

Looking Ahead

Before he applied his technology to peek into cells Lieber recognized the value of using nanowires to build an instant response tool to be used by medical personnel in the analysis of bodily fluids usually extracted for medical lab diagnostics.

In 2007, he helped found Vista Therapeutics to develop a chip using nano-networks that instantly determines the level of different molecules in extracted bodily fluids and enables the detection of certain molecules that currently are not easily detected. Identifying bio-markers in bodily fluids using this tool drastically reduces the time to diagnose an illness.

Vista is very focused on this niche area of “trauma toxic exposure response that can be followed by real-time increases or decreases in bio-markers,” explains Lieber, and, while initial testing may be in animal models, this chip could be used to quickly “record responses to new drugs… [and] speed up pre-clinical tests… bringing a new research tool to pharma, or eventually, clinical [trials].”

Living Nanotechnology

This is just the beginning. Soon, Lieber believes, that, “as we make these devices smaller and smaller” we should be able to merge nanotechnology within living cells in some “hybrid information processing material…with longer range connections in 3-D or powerful prosthetic interfaces, like in the brain.”

Currently, he is designing a network of nanowire circuits and living cells to create an interconnected mesh that could function as a tool for drug development and research. These networks would provide a complex, real-time monitoring of various molecules and cell states to help researchers understand and respond to administered drug interactions and performance at the cellular level.

Exciting, Unknown Future

Lieber’s humble response to being named the top chemist in the world: “I do not know, it is statistics or something… I am not that big on that stuff. At least the people in [my] group are happy. It is a testament to their effort and contribution.”

As Lieber continues his journey leading the chemical world, what will be his main focus in the years to come? “Explore the unknown.” For Lieber, a leap in the dark drives him because he believes that surprises make science interesting. If he already knew the outcome of experiments, “life would not be interesting as a scientist.” Blazing forward with a style that probes the limits of our knowledge, Lieber will keep “pushing boundaries, not entirely sure of the outcome.”